Radical Borylative Cyclization of Isocyanoarenes with N-Heterocyclic Carbene Borane: Synthesis of Borylated Aza-arenes

Article abstract of DOI:10.1021/acs.orglett.1c00309

Borylated aza-arenes are of great importance in the area of organic synthesis. A radical borylative cyclization of isocyanoarenes with N-heterocyclic carbene borane (NHC-BH3) under metal-free conditions was developed. The reaction allows the efficient assembly of several types of borylated aza-arenes (phenanthridines, benzothiazoles, etc.), which are difficult to access using alternative methods. Mild reaction conditions, a good functional-group tolerance, and generally good efficiencies were observed. The utility of these products is demonstrated, and the mechanism is discussed.

Full text of DOI:10.1021/acs.orglett.1c00309

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Letter
Radical Borylative Cyclization of Isocyanoarenes with N‑Heterocyclic
Carbene Borane: Synthesis of Borylated Aza-arenes
Yao Liu,† Ji-Lin Li,† Xu-Ge Liu, Jia-Qiang Wu, Zhi-Shu Huang, Qingjiang Li, and Honggen Wang*
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ABSTRACT: Borylated aza-arenes are of great importance in the
area of organic synthesis. A radical borylative cyclization of
isocyanoarenes with N-heterocyclic carbene borane (NHC-BH3)
under metal-free conditions was developed. The reaction allows
the efficient assembly of several types of borylated aza-arenes
(phenanthridines, benzothiazoles, etc.), which are difficult to
access using alternative methods. Mild reaction conditions, a good
functional-group tolerance, and generally good efficiencies were
observed. The utility of these products is demonstrated, and the
mechanism is discussed.
rganoborons are among the most useful building blocks
Oin organic synthesis due to the versatility of the C−B
bond, which is involved in diverse chemical transformations.1
Interestingly, however, while phenyl-based boronic acids (or
their derivatives) have been met with tremendous success, the
application of heteroaromatic boron reagents is often trouble-
some.2 This is mainly due to their instability, which is derived
from undesired protodeboronation and causes their prepara-
tion to be less efficient.3 For the same reason, their
involvement in cross-coupling reactions is generally less
productive. These statements are particularly true for the
preparation and coupling reactions of 2-heteroaromatic
boronic acids.4 One viable strategy to solve these problems
is to mask the sp2-B boronic acids as tetra-coordinated sp3-
hybridized surrogates. In this regard, MIDA boronates,5a,b
cyclic triolborates,5c and trifluoroborate salts5d display
improved stabilities and are known to undergo efficient
coupling reactions by virtue of the slow-releaseof the free
boronic acids.
For the preparation of heteroaromatic borons, the general
and widely applied method relies on the reaction of a
heteroaromatic metallic reagent (prepared by deprotonation
or metal−halogen exchange) with trialkylborate, wherein a
poor functional group tolerance can be found.6 The direct C−
H borylation of heteroaromatics that was developed in recent
years represents an appealing alternative.7 The prediction of
the regioselectivity, however, remains a challenge. Another
useful strategy is to start with borylated building blocks. By
heterocyclization, the heteroaromatic ring is formed, and the
boryl moiety is retained in the product.8 This strategy offers a
more flexible and diverse synthesis of heteroaromatic borons,
but the availability of borylated building blocks is often limiting
(Figure 1a).
Figure 1. Radical borylative reaction of N-heterocyclic carbene
boranes.
N-heterocyclic carbene boranes (NHC-BH3) have a rich
chemistry and have attracted considerable attention from
organic chemistry community.9 They can seve as precursors of
borenium ions10 and boryl anions.11 Additionally, the ligation
of N-heterocyclic carbenes significantly reduces the bond
Received: January 26, 2021
Published: February 16, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00309
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1891−1897
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dissociation energy of the B−H bond, thus rendering NHC-
BH3 as ideal reagents to generate boryl radicals.12 In this
regard, a variety of carbon−carbon and carbon−heteroatom
multiple bonds, including alkenes,13 alkynes,14 imines,15a
nitriles,15b esters,15c and xanthates,15d are known to undergo
radical addition reactions with NHC-boryl radicals. These
protocols offer convenient access to novel and valuable
borylated building blocks, some of which are otherwise
difficult to prepare (Figure 1b). Nevertheless, although
isocyanides are frequently utilized in radical reactions,16 their
application in the boryl radical-addition reaction is unprece-
dented. Inspired by the recent advances of nitrogen hetero-
cycle synthesis via a radical cascade reaction using isocyanides
as radical acceptors,17 we envisioned that the NHC-boryl
radical may also be added to isocyanide to form an imidoyl
radical, thereby leading to the synthesis of borylated
heteroaromatics. Herein, we show that the strategy is viable
in the synthesis of borylated phenanthridine, benzothiazole,
quinolone, and isoquinoline (Figure 1c). The azo-arenes were
constructed with the concomitant incorporation of a boryl
atom. All these heterocycles are important in functional
molecules,18 but the synthesis and application of their
borylated derivatives have seldom been realized.
With the optimized reaction conditions in hand (Table 1,
entry 3), we next evaluated the substrate scope of this
borylated phenanthridine synthesis. The functional group
compatibility on Ar1 was first investigated. As shown in
Scheme 1, both electron-donating (2b−2h) and electron-
Scheme 1. Scope of Borylated Phenanthridines Synthesis
To start, we investigated the borylative cyclization of 2-
isocyano-1,1′-biphenyl (1a) with 1,3-dimethylimidazol-2-yli-
dene borane (NHC-BH3, 1.5 equiv) (Table 1). The use of di-
a
Table 1. Optimization of the Reaction Conditions
entry
initiator (equiv)
solvent
temperature (°C)
yield (%)
1
2
3
4
5
6
7
8
DTBP
DTBP
DTBP
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
100
120
120
120
120
120
120
120
30
74
78
57
45
35
50
16
b
c
DTBP
DCP
BPO
LPO
TBPB
withdrawing (2i−2p) substituents were well tolerated, giving
the corresponding products in moderate to good yields. 4-
Cyano- and 4-vinyl-substituted isocyanides were also suitable
substrates (2q and 2m, respectively), suggesting a preferential
addition of the NHC-boryl radical to isocyanide and thus a
high chemoselectivity of this protocol.14b,15b Substituents at
the ortho-position did not hamper the reactivity (2r−2t and
2w). The meta-substituted substrates, with two possible
reaction sites, cyclized only at the less sterically congested
position, highlighting a high level of regioselectivity (2u, 2v,
2x, and 2y). This could probably be a result of the large steric-
shielding effect of the NHC-boryl radical. Substrates bearing a
fused arene or heteroarene, such as naphthalene (2z and 2aa),
phenanthrene (2ab), pyridine (2ac), benzofuran (2ad and
2ae), benzothiophene (2af), and indole (2ag), were also viable
for cyclization. The low yield of 2ac might be caused by the
electron- deficiency of pyridine ring compared with the
benzene ring. Interestingly, the reactions of 2z and 2ag
occurred preferentially at the electron-rich position. The
substituent tolerance on Ar2 was also good, as a number of
functional groups with diverse electron properties at different
positions were generally tolerated (2ah−2ao).
a
General reaction conditions are as follows: 1a (0.2 mmol), NHC-
BH3 (0.3 mmol, 1.5 equiv), initiator (1.5 equiv), and solvent (2.0 mL)
in a sealed tube for 12 h under N2. DTBP, di-(tert-butylperoxy)-2-
methylpropane; DCP, dicumyl peroxide; BPO, benzoyl peroxide;
LPO, dilauroyl peroxide; TBPB, tert-butyl peroxybenzoate. NHC-
BH3 (2.0 equiv) was used. Initiator (3.0 equiv) was used.
b
c
(tert-butylperoxy)-2-methylpropane (DTBP, 1.5 equiv) as
initiator and oxidant in toluene at 100 °C produced the
desired borylated phenanthridine (2a) in a 30% yield (Table 1,
entry 1), and with a large amount of NHC-BH3 remained
intact.17,19 Elevating the temperature to 120 °C led to a higher
conversion, and the yield was improved to 74% (Table 1, entry
2). While increasing the loading of NHC-BH3 to 2.0 equiv
further increased the yield to 78% (Table 1, entry 3), the use of
an excess amount of DTBP (3.0 equiv) resulted in a lower
yield (Table 1, entry 4). Other commonly used peroxides, such
as DCP, BPO, LPO, and TBPB, were less effective in
promoting the reaction (Table 1, entries 5−8, respectively).
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The above success encouraged us to explore the applicability
of a similar protocol to other borylated heteroarene syntheses.
Benzothiazoles are a privileged structural motif in medicinal
chemistry.20 The construction of 2-borylated benzothiazoles
would therefore set the stage for the flexible and diverse
synthesis of a benzothiazole-containing small-molecule li-
brary.21 For this purpose, 2-isocyanoaryl thioethers were
chosen as starting materials for cyclization. As a model
reaction, 2-isocyanoaryl thioether (3a, 0.2 mmol, 1.0 equiv)
was reacted with NHC-BH3 (1.5 equiv) in the presence of
different initiators. With DTBP (1.5 equiv), the desired
borylated benzothiazole (4a) was indeed formed in a 23%
yield when the reaction was heated in toluene at 120 °C
(Table 2, entry 1). Varying the dosage of DTBP, however, did
Scheme 2. Scope of the Synthesis of 2-Borylated
Benzothiazoles
a
a
Table 2. Optimization of the Reaction Conditions
a
See the Supporting Information.
6 and 1-borylated isoquinoline 8 were successfully constructed,
but in low yields (Scheme 3).
initiator
(equiv)
additive
(equiv)
temperature
yield
(%)
entry
solvent
(°C)
Scheme 3. Synthesis of Borylated Quinolone and
Isoquinoline
1
2
3
4
5
6
7
8
DTBP (1.5)
DTBP (0.5)
DTBP (3.0)
AIBN (0.5)
AIBN (0.5)
AIBN (0.5)
AIBN (0.5)
AIBN (0.5)
AIBN (0.5)
toluene
toluene
toluene
MeCN
MeCN
toluene
toluene
toluene
toluene
120
120
120
80
80
80
80
80
80
23
22
7
5
RSH (0.5)
RSH (0.5)
RSH (0.2)
RSH (1.0)
RSH (0.2)
58
63
69
39
75
b
9
a
General reaction conditions are as follows: 3a (0.2 mmol, 1.0 equiv),
NHC-BH3 (0.3 mmol, 1.5 equiv), initiator, and additive in solvent
(2.0 mL) in a sealed tube for 8 h. AIBN, 2,2-azobis(isobutyronitrile);
b
RSH, tert-dodecylthiol. NHC-BH3 (2.0 equiv) was used.
To provide insight into the possible mechanism of the
radical borylative cyclization of isocyanoarenes, several experi-
ments were conducted (Scheme 4). First, control experiments
not increase the yield (Table 2, entries 2 and 3). Changing the
initiator from DTBP to AIBN in acetonitrile at 80 °C was
proved to be unfruitful (Table 2, entry 4). Nevertheless, the
introduction of tert-dodecanethiol (0.5 equiv) as a polarity-
reversing catalyst gave a significantly enhanced yield of 58%
(Table 2, entry 5).14b,22 Toluene was a better solvent for this
transformation (Table 2, entry 6). Interestingly, decreasing the
loading of tert-dodecanethiol to 0.2 equiv gave an improved
yield of 69%, while the use of a stoichiometric amount of it was
found to be detrimental to the reaction (Table 2, entries 7 and
8, respectively). Finally, the yield was improved to 75% (Table
2, entry 9) when 2.0 equiv of NHC-BH3 was employed.
The substrate scope of this radical borylative cyclization of
2-isocyanoaryl thioethers was also explored (Scheme 2). A
number of commonly encountered functional groups, such as
ether (4b−4c), cyano (4e), methylsulfonyl (4f), halide (4g, 4h
and 4k), trifluoromethyl (4i), and thioether (4j) groups, were
well tolerated, generally giving the target products in moderate
to good yields. The low yield of 4k is due to the rapid
decomposition of the isocyanide starting material. The ortho-
methyl substituent did not hamper the reactivity (4l and 4m).
Following a similar strategy, isocyanides 5 and 7 were
subjected to the radical cyclization reaction, using DTBP as
both the initiator and the oxidant.23 The 2-borylated quinolone
Scheme 4. Mechanistic Studies
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showed that both reactions were shut down in the absence of
initiators (DTBP or AIBN). TEMPO inhibited both reactions
completely, and a TEMPO-borane (9) adduct was detected
(Scheme 4a and b). These results clearly pointed to a radical
reaction pathway. Unlike the phenanthridine protocol, no
additional oxidant was used for the benzothiazole synthesis.
We were thus interested in the fate of the methyl group in the
2-isocyanoaryl thioethers. To make the detection easier,
compound 10 with a heavier alkyl substituent was prepared
and allowed to react with deuterated NHC-borane (NHC-
BD3). In addition to the desired borylative cyclization product
(4a-D2, 61% yield), an alkylative cyclized benzothiazole 12 was
also formed in a 25% yield (Scheme 4c). Alkane 11 with partial
deuterium incorporation was isolated as the byproduct in a
70% yield. Taken together, these results indicated the
formation of an alkyl radical, probably via homolytic cleavage
of the C−S bond.
Scheme 6. Gram-Scale Synthesis and Synthetic Applications
On the basis of the above results and literature precedents,24
a possible reaction mechanism was proposed and is outlined in
Scheme 5. The boryl radical I is initially generated via
Scheme 5. Proposed Mechanism
In summary, the synthesis of heteroaromatic boron reagents,
especially the 2-heteroaromatic ones, tremendously challeng-
ing. Reported herein is a radical borylative cyclization of
functionalized isocyanides toward the synthesis of 2-borylated
phenanthridines and benzothiazoles. The sp3-B N-heterocyclic
carbene borane (NHC-BH3) is utilized as the boryl source and
offers a high stability to the products. A good functional group
tolerance and moderate to good efficiencies were observed.
The synthetic utilities of the borylated products were
demonstrated. Mechanistic studies suggested a radical reaction
pathway was involved.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00309.
hydrogen abstraction under the assistance of initiator DTBP or
AIBN/RSH. For the synthesis of phenanthridine, the boryl
radical I adds to isocyanide 1 to form a borylimidoyl radical
II,17 which then undergoes intramolecular radical cyclization to
form intermediate III. Finally, the deprotonation and oxidation
of III provide the borylated phenanthridine 2. Likewise for the
benzothiazole synthesis, the borylimidoyl radical IV is initially
formed.22,25 Subsequently, homolytic substitution (SH2) at the
sulfur atom delivers the product 4 and releases an R radical,
which in turn serves as the radical initiator for another cycle of
the reaction.
The synthetic value of the products was also demonstrated
(Scheme 6). First, the efficiency of the multi-millimolar
reaction was not significantly compromised (Scheme 6a).
The oxidation of 2a with Selectfluor (2.2 equiv) gave a
difluoroborate product 13 (Scheme 6b).26 Treating 2a with
hydrogen peroxide gave a C−B bond-oxidized phenanthridin-
6(5H)-one product 14 in good yields (Scheme 6c).27
Interestingly, the reaction of 2a with NCS, followed by an
aqueous workup, led to the formation of the deboron
hydrogenation product 15 (Scheme 6d).26 The palladium-
catalyzed Suzuki−Miyaura coupling reactions of 2a or 4a with
aryl iodides were successful, leading to an extended π-system
(16, 17, and 18) in reasonable yields (Scheme 6e−g,
respectively).26
Complete experimental procedures, characterization of
new products, NMR spectra, HRMS data, and melting
point data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Honggen Wang − Guangdong Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006,
China; orcid.org/0000-0002-9648-6759;
Email: wanghg3@mail.sysu.edu.cn
Authors
Yao Liu − Guangdong Key Laboratory of Chiral Molecule and
Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-
sen University, Guangzhou 510006, China
Ji-Lin Li − Guangdong Key Laboratory of Chiral Molecule and
Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-
sen University, Guangzhou 510006, China
Xu-Ge Liu − Guangdong Key Laboratory of Chiral Molecule
and Drug Discovery, School of Pharmaceutical Sciences, Sun
Yat-sen University, Guangzhou 510006, China;
orcid.org/0000-0003-1878-2525
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Jia-Qiang Wu − Guangdong Key Laboratory of Chiral
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Zhi-Shu Huang − Guangdong Key Laboratory of Chiral
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China; orcid.org/0000-0002-6211-5482
Qingjiang Li − Guangdong Key Laboratory of Chiral Molecule
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00309
Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
́
(e) Rochette, E.; Desrosiers, V.; Soltani, Y.; Fontaine, F.-G. Isodesmic
ACKNOWLEDGMENTS
C−H borylation: Perspectives and proof of concept of transfer
■
borylation catalysis. J. Am. Chem. Soc. 2019, 141, 12305−12311.
This work was supported by the National Natural Science
Foundation of China (nos. 21971261, 21801256, and
81930098), the Key Project of Chinese National Programs
for Fundamental Research and Development
(2016YFA0602900), the Guangdong Basic and Applied Basic
Research Foundation (2020A1515010624), the Fundamental
Research Funds for the Central Universities (19ykpy133 and
20ykzd12), and the Natural Science Foundation of Guangdong
Province (no. 2017A030310511).
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